3-chloro-2-methoxy-2-alkenenitriles



United States Patent 3,547,973 3-CHLORO-2-METHOXY-2-ALKENENITRILES HarryAllen Albrecht, Nutley, and John Thomas Plati, Rutherford, N.J.,assignors to Hoffmann-La Roche Inc., Nutley, N.J., a corporation of NewJersey No Drawing. Original application Apr. 6, 1965, Ser. No. 446,068,new Patent No. 3,400,122, dated Sept. 3, 1968. Divided and thisapplication Nov. 13, 1967, Ser.

Int. (:1. (30% 121/38 [1.5. CI. 26046S.6 2 Claims ABSTRACT OF THEDISCLOSURE Antibacterial N (4 methoxy 3 alkyl isoxazolyl)sulfanilamides, N (4 methoxy 5 alkyl-3- isoxazolyl)sulfanilamides, N (4methoxy 5 alkyl-3- isoxazolyl) sulfanilamides and their base additionsalts with pharmaceutically acceptable bases are described. The N (4methoxy 3 alkyl 5 isoxazolyl)sulfanilamides are prepared from thesequential intermediates 4-methoxy-5-alkylisoxazole,

R-iJOHO N ()CH3 wherein R is hydrogen or lower alkyl, and 5 amino-4-Inethoxy 3 alkylisoxazole. The N (4 methoxy-S- alkyl 3isoxazolyl)sulfanilamides are prepared from the sequential intermediatesOCHa wherein R is hydrogen or lower alkyl, and 3 amino-4-methoxy-S-alkylisoxazole.

CROSS-REFERENCE TO RELATED APPLICATION This application is a division ofUS. patent application Ser. No. 446,068, filed Apr. 6, 1965, now US.Pat. No. 3,400,122 issued Sept. 3, 1968.

(III) 3,547,973 Patented Dec. 15, 1970 BRIEF SUMMARY OF THE INVENTIONThe invention relates to 4 methoxy 5 alkylisoxazoles, 5 amino 4 methoxy3 alkylisoxazoles, and 3 amino 4 methoxy 5 alkylisoxazoles which areuseful intermediates for the corresponding antibacterial N (4 methoxy 3alkyl .5 isoxazolyl)sulfanilamides and N (4 methoxy 5 alkyl 3isoxazolyl) sulfanilamides.

In another aspect, the invention relates to intermediates of theformulas 0 R-ii CHO EN and RC Cl=C wherein R is hydrogen or lower alkyl.

DETAILED DESCRIPTION This invention relates to sulfonamides and moreparticularly relates to sulfonamides of the formulas and to methods fortheir preparation. In the above formulas R is hydrogen or lower alkyl.

Compounds of Formulas I and II are prepared according to the followingreaction schemes:

Reaction Scheme I EB NHZOH'H 0 CH lower alkoxide l or hydroxide O OH(VII) NHzOH I 1. YQ-SOQZ (IX) l 2. alkali metal hydroxide 3. conversionof Y to NH2, if necessary In the above Reaction Schemes I and II, R ishydrogen or lower alkyl, X is chlorine or bromine, preferably chlorine,and Y is a protected amino group or an amino group precursor, i.e., agroup which can be converted to an amino group through reduction orhydrolysis, for example, nitro, nitroso, azo, hyrazo, hydrazido,carbalkoxyamino, carbobenzyloxyamino, etc., or preferably an acylamidogroup, for example, an alkanoylamido group, preferably a loweralkanoylamido group, e.g., acetamido, propionylamido, etc., or abenzamido or substituted benzamido group, e.g., alkylor halo-substitutedbenzamido.

In Reaction Scheme I a methoxy methyl ketone of Formula III is reactedwith dimethyl formamide (IV) in the presence of phosphorus oxychlorideor phosgene, preferably at a temperature in the range of from about toabout 100 C. to form a mixture of aldehydes of Formulae Va and Vb. Thismixture of aldehydes is then reacted with a mineral acid addition saltof hydroxylamine, e.g., hydroxylamine hydrochloride, hydroxylaminesulfate, etc., preferably at a temperature in the range of from about toabout 85 C., and preferably in an inert solvent, e.g., a lower alkanolsolvent such as methanol, ethanol, etc., to form a 4-methoxy-5-loweralkyl isoxazole of Formula VI. Compound V1 is reacted with an alkalimetal lower alkoxide, e.g., sodium methoxide, sodium ethoxide, etc., oran alkali metal hydroxide, e.g., sodium hydroxide, potassium hydroxide,etc., preferably at a temperature in the range of about 20 to about 65C. to form a ketonitrile of Formula VII. The ketonitrile of Formula VIIis reacted with a mineral acid addition salt of hydroxylamine, e.g.,hydroxylamine hydrochloride, etc., preferably in the presence of water,to form an aminoisoxazole of Formula VIII. This aminoisoxazole is thentreated with a sulfonyl halide of Formula IX in the presence of an acidbinding agent such as an amine, e.g., pyridine, trimethylamine, etc., toform a sulfanilyl compound. The latter is treated with an aqueous alkalimetal hydroxide, e.g., sodium hydroxide, potassium hydroxide, etc.; andfinally the Y group is converted to amino, if necessary, by a knownprocedure in the sulfonamide art. Where Y is a group hydrolyzable toamino such as acetamido, hydrolysis of the hydrolyzable group takesplace upon treatment with the alkali metal hydroxide to yield a compoundof Formula I directly. However, where Y is an amino group precursorwhich is reducible to an amino group, then a standard reduction reactionsuch as hydrogenation with a palladium catalyst, is carried out to givea compound of Formula I.

Compounds of Formula II are prepared according to Reaction Scheme II bytreating a mixture of aldehydes of Formulae Va and Vb with hydroxylamineunder alkaline conditions, i.e., in the presence of a base, e.g., analkali metal carbonate such as sodium carbonate, an alkali metalhydroxide such as sodium hydroxide, potassium hydroxide, etc., an alkalimetal lower alkoxide such as sodium methoxide, sodium ethoxide, etc., toform an oxime of Formula X (which is probably a mixture of cistransisomers). The oxide of Formula X is dehydrated by the use of phenylisocyanate, preferably in the presence of an inert hydrocarbon solvent,e.g., benzene, toluene, hexane, etc., at a temperature in the range ofabout 20 to about to form a nitrile of Formula XI. The nitrile ofFormula XI is then reacted with hydroxylamine under alkaline conditions,e.g., in the presence of an alkali metal hydroxide such as sodiumhydroxide, potassium hydroxide, etc., an alkali metal lower alkoxidesuch as sodium methoxide, sodium ethoxide, etc., to form anaminoisoxazole of Formula XII. The aminoisoxazole of Formula XII is thenreacted with a sulfonyl halide of Formula IX in the presence of an acidbinding agent such as an amine, e.g., pyridine, trimethylamine, etc., toform a sulfanilyl derivative which is treated with an alkali metalhydroxide as above, and the Y group converted to NH if necessary (asdescribed about for Reaction Scheme I) to form a compound of Formula II.

Preferred compounds of Formulae I and II are those wherein R is methyl.

The term lower alkyl used herein is to be understood to refer to analkyl group having from 1 to 7 carbon atoms, which can be eitherstraight or branched chain, e.g., methyl, ethyl, propyl, isopropyl,butyl, heptyl, hexyl, etc.

Compounds of Formulae I and II and their base addition salts withpharmaceutically acceptable bases, such as sodium hydroxide,diethanolamine, etc., are antibacterial agents useful in the same manneras known sulfonamides, e.g., sulfadimethoxine. They are characterized bya wide spectrum of antibacterial activity. They can be employed in oralor parenteral dosage forms or for topical application such as in salves,otic formulations, etc., in combination with common pharmaceuticaladjuvants. Typical dosage forms are given below:

TABLET FORMULATION Mg. per tablet N -(4-methoxy-3-methyl 5 isoxazolyl)sulfanilamide 505 Corn starch 29 Lactose 84 Gelatin 12 Talcum 15Magnesium stearate 5 PROCEDURE (1) N -(4-methoxy-3-methyl 5isoxazolyl)sulfanilamide, corn starch, and lactose were thoroughly mixedin suitable blending equipment and granulated with a 10 percent gelatinsolution.

(2) The moist mass was passed through a N0. 12 screen, and the granuleswere dried on paper lined trays overnight.

(3) The dried granules were passed through a No. 14 screen and placed ina suitable mixer. The talcum and magnesium stearate were added andblended.

(4) The granulation was compressed into tablets weighing approximately650 mg. each, using punches having an approximate diameter of 12.7 mm.The final tablet thickness was about 5.35 mm.

PARENTERAL FORMULATION Mg./cc.

N -(4-methoxy-3-methyl-5-isoxazolyl)- sulfanilamide 412.0 Diethanolamine159.0 Sodium metabisulfite 2.0

Water for Injection USP q.s. ad 1.0 cc.

PROCEDURE l) The sodium metabisulfite was dissolved in the water forinjection in a suitable size glass container (glasslined container mayalso be used).

(2) Successive portions of the N -(4-methoxy-3-methyl-S-isoxazolyl)sulfanilamide were suspended in the solution anddissolved by the addition of somewhat less than the equivalent quantityof diethanolamine until the required concentration solution was reached.

(3) The solution was filtered through a filter press to remove the grossparticles, and then through a No. 015 candle to achieve final clarityand sterility.

(4) The solution was filled under aseptic conditions into 5 cc. ambervials, sealed, and sterilized for 20 minutes at 250 F.

(5) The ampuls were inspected, and any ampuls showing insoluble materialwere rejected.

TABLET FORMULATION Mg. per tablet N -(4-methoxy-5-methyl-3-isoxazolyl)-sulfanilamide 505 Corn starch 29 Lactose 84 Gelatin 12 Talcum 15Magnesium stearate 5 PROCEDURE 1) N(4-methoxy-5-methyl-3-isoxazolyl)sulfaniliamide, corn starch, andlactose were throughly mixed in suitable blending equipment andgranulated with a percent gelatin solution.

(2) The moist mass was passed through a No. 12 screen, and the granuleswere dried on paper lined trays overnight.

(3) The dried granules were passed through a No. 14 screen and placed ina suitable mixer. The talcum and magnesium stearate were added andblended.

(4) The granulation was compressed into tablets weighing approximately650 mg. each, using punches having an approximate diameter of 12.7 mm.The final tablet thickness was about 5.35 mm.

PAIRENTERAL FORMULATION Mg./cc.

N 4-methoxy-5-methyl-3 -isoxazolyl) sulfanilamide (claim 400 mg.) 412.0Diethanolamine 159.0 Sodium metabisulfite 2.0

Water for injection USP q.s. ad 1.0 cc.

PROCEDURE (1) The sodium metabisulfite was dissolved in the water forinjection in a suitable size glass container (glasslined container mayalso be used).

(2) Successive portions of the N -(4-methoxy-5-methyl-3-isoxazolyl)sulfanilamide were suspended in the solution anddissolved by the addition of somewhat less than the equivalent quantityof diethanolamine until the required concentration solution was reached.

(3) The solution was filtered through a filter press to remove the grossparticles, and then through a No. 015 candle to achieve final clarityand sterility.

(4) The solution was filled under aseptic conditions into 5 cc. ambervials, sealed, and sterilized for 20 minutes at 250 F.

(5) The ampuls were inspected, and any ampuls showing insoluble materialwere rejected.

The following examples are given for illustration purposes only and arenot meant to limit the invention.

EXAMPLE 1 Preparation of N -(4-methoxy-3-methyl-5- isoxazolyl sulfa nilamide N,N-dimethylformamide (438 g.) was cooled in an ice-salt bathwhile phosphorus oxychloride (452 ml.) was added at 2-5 with vigorousstirring over a period of two hours. The cold bath was removed and thereaction stirred for 30 minutes, during which time the temperature roseto 15. The mixture was then warmed momentarily on a water bath and thetemperature maintained at 20-24" for 30 minutes.

With cooling below 10 mcthoxyacetone (176 g.) was added over a period of25 minutes and the bath was removed to permit a spontaneous heatgeneration. Within 15 minutes the temperature reached 35 and was controlled at 3540 for 35 minutes by intermittent cooling. The mixture waspoured into 2 kg. of cracked ice. Sodium chloride (400 g.) was added andthe mixture allowed to warm to 15. While maintaining the temperaturebetween 15 and 22 by intermittent cooling with an ice bath, the mixturewas extracted with three 1200 ml. portions of ether. The ether extractswere combined and washed successively with saturated sodium chloride(400 ml.), saturated sodium bicarbonate solution (400 ml), and finallywith saturated sodium chloride solution (250 ml.). After drying withsodium sulfate, the ether solution was concentrated on the steam bathand the residue distilled; yield of a cis-trans mixture of3-chloro-2-methoxy-2- butenal, 142 g.; boiling point 70-80/20 mm.

3-chloro-2-methoxy-2'butenal (cis-trans mixture) g.), hydroxylaminehydrochloride (77.5 g.), and methanol (750 ml.) were refluxed for twohours. When the mixture had cooled to 40 a solution of cadmium chloride(450 g. of CdCl -Z /zH O) in water (400 ml.) was added. The cadmiumchloride complex was allowed to crystallize overnight before filteringand washing with methanol and ether.

The complex (21.8 g.) was mixed with 100 ml. of water and distilled,collecting about 50 ml. of distillate consisting of two phases. Thedistillate was saturated with sodium chloride and extracted with five 10ml. portions of ether. The ether was dried with sodium sulfate anddistilled on the steam bath. The residue, 4-methoxy- S-methylisoxazole(6.1 g.), was distilled under reduced pressure; yield 4.81 g.; boilingpoint 108/100 mm.

4-methoxy-S-rnethylisoxazole (4.81 g.) was added to a solution of sodiummethoxide (4.60 g.) in methanol (50 ml.) with momentary cooling to keepthe reaction temperature below 40. At this point the sodium salt of theketonitrile partially precipitated, but was allowed to remain in themixture. After standing for one hour, the methanol was evaporated invacuo. Water (10 ml.) and hydroxylamine hydrochloride (2.98 g.) wereadded, and the mixture was warmed to 60 for 30 minutes. After standingfor about 16 hours at room temperature, the mixture was extracted withfive 10 ml. portions of ether. The ether extracts were dried with NaSOand evaporated in vacuo to leave a 4.90 g. residue. Crystallization fromether (10 ml.) and petroleum ether (2 ml.) in an icesalt bath gave themajor portion of product, 5-amino-4- methoxy-3-methylisoxazole, 3.30 g.,melting point 4849.

The filtrate was evaporated, and the residue crystallized from ether (2ml.) and petroleum ether (1 ml.) to obtain a second crop: 0.95 g.,melting point 4849. Total yield, 4.25 g.

5-amino-4-methoxy 3 methylisoxazole (3.75 g.) was dissolved in drypyridine (38 ml.) and p-acetylaminobenzenesulfonyl chloride (15.1 g.)was added. On stirring into solution the reaction temperature rose to 40where it was maintained by warming for 1 /2 hours.

The mixture was cooled to room temperature, and diluted with water (375ml.). The oily precipitate was left standing overnight to solidify. Thecrude product, a bis(p-acetylaminobenzenesulfonyl) compound (14.35 g.,darkens at 190, melts 224225) was used directly.

A sample purified for analysis by crystallization from acetic acidmelted at 233234.

The bis(p acetylaminobenzenesulfonyl) compound (14.35 g.) and 144 ml. of10 percent w./w. aqueous sodium hydroxide were stirred and heated on thesteam bath for 40 minutes. Cooling and treatment with 25 percent aqueouacetic acid ml.) precipitated the product (7.20 g., melting point166-169). Crystallization from methanol (50 ml.) and water (100 ml.)gave the pure product, N-(4-methoxy-3-methyl-5-isoxazolyl)sulfanilamide; yield 6.88 g.; meltingpoint 168-170.

EXAMPLE 2 Preparation of N -(4-methoxy-5-methyl- 3 -isoxazolyl)sulfanilamide 3-chloro 2 methoxy 2 butenal (cis-trans mixture) (122.0g.) was added with stirring to a solution of hydroxylamine hydrochloride(70' g.) and sodium hydroxide (40 g.) in 1 liter of water. The reactionwas stirred two hours, and the crude product filtered (101.4 g., meltingpoint 68-85"). This material consisted of a mixture of isomers of3-chloro-2-methoxy-2-butenal oxime.

Crystallization from ether (100 ml.) and petroleum ether (400 ml.)yielded the isomer formed as the major product; yield 59.3 g.; meltingpoint 9l94.

Further recrystallization for analysis gave a melting point of 95-96".

Evaporation of the filtrate and trituration of the residue withpetroleum ether gave a mixture enriched in the second isomer (29.5 g.,melting point 5267 Further crystallization of a similarly obtainedmaterial gave a product, which still contained approximately one-thirdof the higher melting isomer.

3-chloro-2-methoxy-2-butenol oxime (melting point 91-94) (59.3 g.) wasadded to a solution of phenyl isocyanate (94.5 g.) and triethylamine(3.5 ml.) in benzene (600 ml.). After stirring for minutes, the mixturewas cautiously heated on the steam bath and refluxed 2 /2 hours.

The mixture was cooled, and the precipitate of syrn. diphenylurea wasfiltered. The benzene solution was concentrated on the steam bath, andthe residue, 3-chloro- 2-methoxy-2-butenenitrile, distilled in vacuo;yield 32.5 g.; boiling point 5962/20 mm.

A mixture of 3-chloro-2-methoxy-2-butenenitrile (21.0 g.), hydroxylaminehydrochloride (16.8 g), sodium methoxide (21.6 g.), and methanol (200ml.) was stirred at 40 for 18 hours. The mixture was filtered and thefiltrate evaporated to dryness in vacuo. The residue was extracted withwarm ether (200 ml.). The ether solution was evaporated in vacuo and theresidue, 3-amino-4methoxy-5-methylisoxazole (15.6 g.) crystallized fromether (20 ml.) at 10 to give the major portion of the product (1.05 g.,melting point 9092).

A further amount of aminoisoxazole was recovered from the filtrate. Theresidue after evaporation of the ether was vigorously shaken with water(140 ml.), centrifuged, and the aqueous solution decanted. Evaporationof the water left a residue (4 g.) which crystallized from ether (6 ml.)at 10 to give additional product (0.43 g., melting point 85-89"). Totalyield, 1.48 g.

A sample purified by recrystallization from ether melted at 9193.

3-amino-4-methoxy-S-methylisoxazole (1.35 g.) was dissolved in drypyridine (13.5 ml.), and p-acetylaminobenzenesulfonyl chloride (5.42 g.)was added. On stirring into solution, the temperature rose to 40, whereit was maintained by warming for 1 /2 hours. The mixture was cooled, anddiluted with water (140 ml.). The precipitate, abis(p-acetylaminobenzenesulfonyl) compound, solidified on standingovernight (4.82 g., melting point 230 235). Recrystallization of asample from acetic acid raised the melting point to 239241.

The bis product (4.82 g.) and ml. of 10 percent w./w. aqueous sodiumhydroxide were stirred on the steam bath for one hour. Cooling andtreatment with 25 percent acetic acid (35 ml.) precipitated the productN (4-methoxy-S-methyl-3-isoxazolyl)sulfanilamide (2.00 g., melting pointl89191), which was recrystallized from methanol (40 ml.) and water (120ml.); yield 1.83 g.; melting point 197199.

We claim:

1. A compound of the formula /CN RGC1=C OCH;

wherein R is selected from the group consisting of hydrogen and loweralkyl.

2. A compound according to claim 1, wherein R is methyl, i.e.,3-chlor0-2-methoxy-2-butenenitrile.

References Cited UNITED STATES PATENTS 2,326,373 8/1943 Long 2 465.6

JOSEPH P. BRUST, Primary Examiner

